Acylation is a process frequently used in the chemical arts to introduce one or more carbonyl-containing substituents into a compound of interest, often to protect hydroxyl or amine groups. Over the years, investigators have identified a variety of reagents and reaction conditions for acylating particular functionalities. Of particular interest is the ability to selectively acylate a desired functionality without the need to protect and deprotect other reactive sites thereby creating a more efficient synthetic scheme.
For example, Ishihara et al. describe a method for selectively acylating a primary alcohol in presence of secondary alcohols using an acyl chloride (Ishihara et al. (1993) J. Org. Chem. 58: 3791-3793). In an exemplary reaction scheme, a 1:1 mixture of 1-octanol and 2-octanol in methylene chloride was reacted with acetyl chloride in the presence of various bases, for example, 2,4,6-collidine, N,N-diisopropylethylamine, or 1,2,2;6,6-pentamethylpiperidine. Under the conditions described, the primary alcohol in 1-octanol was acylated preferentially over the secondary alcohol in 2-octanol.
Garegg et al. similarly describe the regioselective acetylation of the primary alcohols of a tetrasaccharide in the presence of its secondary alcohols (Garegg (1997) J. Carbohydr. Chem. 16(7): 973–981). Specifically, Garegg et al. utilize an excess of acetyl chloride and collidine in methylene chloride at low temperature (−70° C.) to perform the selective acetylation.
In another example, Szeja identified reaction conditions to selectively acylate a secondary hydroxyl group at either the 2-position or the 3-position in a sugar molecule where both hydroxyl groups are initially unprotected (Szeja (1979) Synthesis 821–822). In the paper, Szeja reports that methyl 4,6-O-benzlidene-a-D-galactopyranoside was partially esterified in 46% yield at its more reactive 3-hydroxyl group using benzoyl chloride and pyridine (see, e.g., Haines (1976) Adv. Carbohydr. Chem. Biochem. 33: 11). However, Szeja discloses the regioselective benzoylation of methyl 4,6-O-benzlidene-a-D-galactopyranoside at either its 2-hydroxyl group or its 3-hydroxyl group via phase transfer catalysis.
More specifically, when benzoyl chloride was added to methyl 4,6-O-benzlidene-a-D-galactopyranoside in benzene and hexamethylphosphoric triamide with tetrabutylammonium chloride and a 40% aqueous sodium hydroxide solution forming the aqueous phase, the reaction provided the 3-O-benzoyl product in a 62% yield. In contrast, when benzoyl chloride was added to methyl 4,6-O-benzlidene-a-D-galactopyranoside in the same phase transfer catalysis system without the hexamethylphosphoric triamide present, the reaction provided the 2-O-benzoyl product in a 69% yield.
Regarding the acylation of taxanes, U.S. Pat. Nos. 5,319,112 and 5,470,866 describe reaction conditions for acylating the hydroxyl groups at the C-2′ positions of the taxane molecules paclitaxel and dihydrocephalomannine. In the reactions, a mixture of paclitaxel and dihydrocephalomannine dissolved in acetonitrile was combined with benzoic acid, dicyclohexylcarbodiimide and 4-(N,N-dimethylamino)pyridine. The reaction resulted in benzoylation of the C-2′ position of paclitaxel and dihydrocephalomannine. Taxane molecules acylated at the C-2′ position reportedly are useful starting materials for producing oxalate and oxamido derivatives of taxanes (se U.S. Pat. No. 5,470,866).
Paclitaxel, also known as taxol A (TAXOL® being a registered trademark of the Bristol-Myers Squibb Company), is a member of the taxane family, and is a naturally occurring diterpenoid. Paclitaxel has been shown to have great value as an anti-cancer drug. Paclitaxel can be isolated from certain yew trees, for example, Taxus brevifolia, and certain species of Taxus media (e.g., species known as “Hill,” “Hicksii” and “dark green spreader”) (see U.S. Pat. No. 5,744,333), extracted from cell cultures, or synthesized completely or partially in vitro. Notwithstanding these methods, the global supply of paclitaxel has been quite limited, and there is an ongoing need for other methods for producing paclitaxel cost effectively on a larger scale.
Because of the promising clinical activity of certain taxanes (e.g., paclitaxel) against various types of cancer, there is an ongoing need for different methods for preparing paclitaxel and other taxane molecules, including paclitaxel derivatives and analogues. There also is a need for paclitaxel derivatives having a range of in vivo and in vitro activities, as well as paclitaxel derivatives having similar biological activities to paclitaxel. It is believed that the preparation of paclitaxel analogues may result in the synthesis of compounds with comparable or greater potency, superior bioavailability, or fewer side effects than paclitaxel. In support of this approach, a paclitaxel analogue known as docetaxel (TAXOTERE®) has been identified.
Docetaxel, which differs from paclitaxel only in the nature of the N-acyl substituent and the absence of a 10-acetyl group, is reported to be twice as active as paclitaxel in certain assays (see U.S. Pat. No. 5,319,112). It is contemplated that other paclitaxel derivatives not yet identified may have other beneficial and pharmacologically desirable properties. Furthermore, there is also need for paclitaxel analogues that can be used as taxane standards. For example, it is desirable to make easily synthesizable analogues that can be used for characterizing structure-activity relationships of taxane molecules, as chromatography standards, or starting or intermediate molecules in the synthesis of various other taxane molecules.